Acute kidney injury (AKI) varies from 5% in all hospitalized patients to 30?50% in intensive care units. The proximate cause of the injury appears to be multifactorial, whether the etiology of AKI is ischemic, septic, toxic or some combination of the three. However, there is increasing evidence for an important role in AKI for both resident and infiltrating macrophages to initiate and exacerbate renal injury by polarization to a pro- inflammatory or ?classically activated? (?M1?) phenotype. An unanswered question is: What are the triggers to activate quiescent resident macrophages and monocytes to an M1 phenotype following an episode of AKI? Studies by us and others have also recently demonstrated important roles for tissue reparative or ?alternatively activated? (?M2?) macrophages in the recovery from AKI. M2 macrophages are phagocytes and play an important role in the phagocytosis of apoptotic epithelial cells as well as apoptotic neutrophils (?efferocytosis?). There is evidence that when apoptotic cells are not phagocytized, they may eventually rupture and release their cellular contents, a process known as ?secondary necrosis?, and these cellular contents may activate viable epithelial cells and infiltrating cells through Fc receptors and toll like receptors (TLRs) and induce inflammatory cytokines. We propose that the failure of renal macrophages to effectively perform these functions is an important factor mediating development of continued inflammation and ineffective repair, which can lead to development of chronic renal insufficiency and we will address: How do M2 macrophages/dendritic cells promote renal epithelial cell repair following AKI? Alterations in metabolism play an important role in polarization of macrophages. M1 macrophages utilize predominantly glucose and glutamine as metabolic substrates, have increased aerobic (?Warburg?) glycolysis and exhibit defects in the Krebs cycle such that there is increased isocitrate, succinate and arginine production. Still unexplored is: What is the role of alterations in immunometabolism in acute kidney injury? There is also increasing evidence that apparent functional recovery from episodes of AKI can be incomplete, even if BUN and serum creatinine levels return toward normal, and the post-AKI kidney is at increased risk both for further injury and for the development of CKD. We will determine if activated, profibrotic renal M2 macrophages play a key role in development of fibrosis in the later stages of recovery from AKI? To answer these questions, we propose three specific aims: Aim 1 Determine the Mechanisms Underlying Development and Action of Proinflammatory Macrophages in Acute Kidney Injury Aim 2 Determine the Role of Immunometabolism in Acute Kidney Injury Aim 3 Determine Mechanisms Mediating Macrophage Promotion of Post-AKI Tubulointerstitial Fibrosis !